CLL INTRODUCTION: Treatments

The most important step in the management of patients with chronic lymphocytic leukemia (CLL) is to confirm that the diagnosis is accurate. Mantle cell leukemia, splenic lymphoma with villous lymphocytes or marginal zone lymphoma in a leukemic phase can be misdiagnosed as CLL. The diagnosis must be confirmed by an experienced hematopathologist who looks at the characteristics of the cells and confirms with a flow cytometry panel evaluating proteins on the surface of the cells. CLL is diagnosed when there is expression of proteins CD5, CD19, CD20, and CD23. The next step is to stage the patients with examination of the lymph glands, liver and spleen. CAT scans are taken if considered necessary by the doctor. Bone marrow aspiration and biopsy is not essential but is often useful in considering likelihood of progression.

The first decision regarding treatment

Not all patients require treatment. Many have a benign accumulation of CLL cells and never suffer any consequences of the diagnosis of CLL. These patients are classified as having "smoldering" CLL and have a hemoglobin greater than 13gm/dl, a platelet count greater than 150,000, a lymphocyte count of less than 25,000 with minimal evidence of enlargement of lymph nodes or spleen. If the white cell count does not double in one year, such "smoldering" CLL patients have a survival the same as if they never had the disease.

Patients requiring therapy initially are those with large lymph glands or spleen, or lower hemoglobins or platelet count. The other patients are put on a "watch and wait" approach ("watch and worry" for patients). A number of patients with minimum CLL get debilitating fatigue, sweats, or difficulty in concentration. These symptoms can occur early and are often treated with a rituximab regimen. Other patients are observed until they develop progression of the disease such as a fall of hemoglobin levels, platelet counts, increasing lymph node or spleen size, doubling time of the white cell count of less than one year, or development of symptoms, and then treatment is warranted.

Frontline Treatment for CLL for Patients fulfilling National Cancer Institute (NCI) Working Group Criteria for Treatment

Formerly, there were very few options to apply to patients. However, we have now progressed from chlororambucil (leukeran) with or without prednisone which can achieve a complete remission (CR) of 3–5% to fludarabine with a CR of 25% to FC (fludarabine–cyclophosphomide) with a CR of 35–40%, FR (fludarabine–rituximab) with a CR of 47% and FCR (fludarabine–cyclophosphomide–rituximab) with a CR rate of 70%. Studies have shown: Fludarabine is superior to chlorambucil in all age groups, FC is superior to fludarabine, and FR is superior to F, and FCR is in the process of being compared to other regimens. In all other leukemias, the higher the CR rate, the more likely patients are to have prolonged remissions on any particular treatment. When investigators at M. D. Anderson Cancer Center compared fludarabine alone to FC to FCR, there was a very significant improvement in survival of patients treated with FCR compared to the other treatment regimens.

The Goal of treatment these days is a high CR rate with no evidence of minimum residual disease (MRD) as measured by specific flow cytometry or a polymerase chain reaction (PCR) for the immunoglobulin gene, which is the fingerprint of the CLL. MRD negative patients are likely to have an 80–90% chance in remissions longer than five years.

Transplantation

Autologous stem cell transplantation (SCT) using a patient's own stem cells has not been demonstrated to cure patients but has the prospect of prolonging their remissions. The most promising area in transplantation is in the area of allogeneic marrow or peripheral blood SCT (using donor stem cells) where patients receive modest chemo immunotherapy (non myeloablative stem cell transplants, NST). The infused immune cells from the donor attack the CLL cells. The prospect of long–term control is very real with NST but extended follow–up will be necessary. The addition of rituximab to preparative regimens has markedly improved the outcome and decreased toxicity. The exact timing and place of NST following initial therapy is not clear at the present time, but as the technology improves it will be brought earlier into the treatment strategy.

Relapsed CLL

In the relatively few publications on treatment of relapsed CLL, it has become clear that fludarabine is useful in patients who are resistant to chlorambucil. The combination FC is superior to F in terms of response rate. The FCR regimen is very significantly superior and has been shown in the multi–variate analysis to be the optimal treatment at M. D. Anderson Cancer Center. Comparative trials of FCR versus FC are being conducted in Europe at the present time.

Early intervention of early stage patients

Patients who would not normally be considered for treatment but can now be identified to have adverse prognostic factors such as unmutated immunoglobulin genes, high ZAP70, high β2–microglobulin or abnormalities in chromosome 17p are now being considered for early intervention. While it has been established that these factors are associated with a shorter time to initiating therapy and a shorter survival, it has not so far been established that early intervention is likely to lead to improved outcome.

Emerging new strategies

A potent but toxic treatment called flavopiridol may be the next major new drug in CLL and clofarabine is showing activity.

A major interest in CLL is in the area of new monoclonal antibodies. Three antibodies being studied involve CD23, CD40 and CD22 pathways. These antibodies are called lumiliximab, HCD122, and epratuzamab respectively. These new agents will need to be blended into the other effective treatments.

Goal of therapy

While formerly the goal of treatment was strictly symptom management, the possibility of curative strategies is already in play. It is quite possible that with the high CR rates found in recent studies, some of these patients will be cured. It is clear that residual disease can be suppressed by interventions while the patient is in clinical remission. This will lead to prolongation of remission. Optimism is the new key word for the rapidly improving outcome of patients and our improved ability to more clearly identify patients who have good and bad risk characteristics.

Presently, the goal of treatment is a high CR rate with no evidence of minimal residual disease (MRD) as measured by specific flow cytometry or a polymerase chain reaction (PCR) for the immunoglobulin gene, which is the fingerprint of the CLL. This approach has the highest likelihood of significantly prolonging survival.